Background:    Grade IV astrocytoma, or glioblastoma multiforme (GBM), is among the most commonly aggressive gliomas resistant to treatment approaches. There is a high expression of glycolytic genes in clinical glioblastoma patients that was reported to correlate with decreased patients' survival. Both 3-bromopyruvate (3BP) and citrate are promising glycolysis inhibitors and anticancer agents with many wonderful mechanisms of anticancer effects. Glucose is the substrate of hexokinase while glucose-6-phosphate is the substrate of phosphofructokinase, PFK. 3BP is a hexokinase inhibitor while citrate is a PFK inhibitor.
Objectives: This study aims at investigating the effects of adding the first two substrates of glycolysis (glucose and glucose-6-phosphate) affecting the survival of C6 glioma cells, which were reported to be maximally killed using either 9 mM citric acid or 60 μM 3BP.
Materials and methods: MTT viability assay was performed to C6 glioma cells.
Results: Glioma cell death was significantly and maximally induced by 3BP and citrate. The addition of glucose or glucose-6-phosphate in successive doses did not prevent the mortality of C6 glioma cells caused by 3BP. Adding serial doses of glucose did not protect against citrate-induced C6 glioma cell death. However, the most interesting finding in this study was that citrate-induced glioma cell death was quite inhibited via adding serial doses of glucose-6-phosphate.
Conclusion: Glucose-6-phosphate antagonized citrate effects on glioma cell viability possibly via activating the glycolytic enzyme PFK. PFK is well-known to be inhibited by citrate and that citric acid is a structural analog of glucose-6-phosphate. This finding is quite important as citrate toxicity can be inhibited via adding glucose-6-phosphate.